Angiogenesis is a mechanism in which new blood vessels are generated from existing blood vessels by growth, division, migration, and the like, of endothelial cells. The angiogenesis plays an important role in the normal growth process including wound healing or female menstrual cycles. However, abnormal angiogenesis is known to play a crucial role in diseases, such as macular degeneration (MD), diabetic retinopathy, cancer growth and metastasis, psoriasis, rheumatoid arthritis, and chronic inflammation (Risau. Nature. 386(6626):671-674 (1997), and Carmeliet and Jain. Nature. 407(4801):249-257 (2000)).
A vascular endothelial growth factor (VEGF) is a representative angiogenesis inducing factor. VEGF is an important factor that regulates not only adult angiogenesis but also vasculogenesis in the embryonic development. Five types of VEGF (VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PLGF) have been revealed to this date, and these are known to bind to VEGF receptors (VEGFRs) 1, 2 and 3, and co-receptors, such as heparin sulphate proteoglycans (HSPGs) and neuropilins (NRPB).
It is known that VEGF binds to VEGFR1 and VEGFR2, among several types of receptors, with very high affinity, and induces an angiogenic mechanism, such as proliferation and migration of vascular endothelial cells, mainly through VEGFR2. Therefore, VEGF and VEGFR2 have been major targets for inhibiting angiogenesis-related diseases (Ellis and Hicklin. Nat Rev Cancer. 8(8):579-591 (2008); Youssoufian et al. Clin Cancer Res. 13(18Pt2):5544s-5548s. (2007)).
Ramucirumab, which is an antibody that has been used and approved among antibodies targeting VEGFR2, is commercialized as CYRAMZA, and many studies thereof have been conducted. Ramucirumab, which is a monoclonal antibody selected from the full human Fab library, has been approved for use in colon cancer, non-small cell lung cancer, and stomach cancer (Spratlin et al. J Clon Oncol. 28(5):780-787 (2010); Spratlin et al. Future Oncol. 6(7):1085-1094 (2010); Aprile et al. Drugs. 73(18); 2003-2015 (2013); and Chan et al. Biologics. 22(9):93-105 (2015)).
Throughout the specification, many papers and patent documents are used as references, and the citations thereof are represented. The disclosure of the cited papers and patent documents is incorporated in the present specification by reference in its entirety, to describe a level of a technical field to which the present invention pertains and content of the present invention more clearly.